A pharmaceutical product used for clearance of the bowel prior to X-ray examination, endoscopy or surgery, is presently sold under the trade mark name of PICOLAX™. The pharmaceutical product is a white powder which is made up as a solution (in water) for administration. The properties required are that it is a strong laxative that is easily palatable. The pharmaceutical product includes sodium picosulphate (PS), a stimulant laxative; and anhydrous citric acid (CA) and magnesium oxide (MgO, light), which together in solution form magnesium citrate, an osmotic laxative with a powerful cathartic effect.
The dosage form for oral delivery is in the form of granules. Herein the term granule(s) includes loose particles (such as particles which might collectively be termed a powder, including loose particles in the form of a powder which is known in the art as “powder for oral administration”). The product is a physical mixture of six raw materials; these being citric acid (e.g. citric acid anhydrous or citric acid monohydrate), magnesium oxide (e.g. magnesium oxide light), potassium bicarbonate (KHCO3), sodium picosulphate (NaPIC), sodium saccharin, and orange flavour. Magnesium oxide “light” means, herein, magnesium oxide having an apparent volume such that 15 g occupies between 75 to 180 ml, e.g 15 g occupies a volume of 150 ml.
The known process for making PICOLAX™ may include the following steps. Granules of magnesium oxide and citric acid are produced by mixing the two reagents together—this is known as the “primary mix”. In another stage, potassium bicarbonate, sodium picosulphate and water are mixed or blended to produce a wet “pre-mix”, which is then dried. In a further stage, the flavour ingredients, orange flavour and sodium saccharin, are blended with the pre-mix and primary mix. The known process has several associated problems.
Firstly, the mixing processes may result in inhomogeneity problems in the final and intermediate products. In one aspect, the terms “inhomogeneity” and “lack of homogeneity” as used in this application refer to the lack of uniformity of content of the active substance—sodium picosulphate—in e.g. the final product. It also refers to the lack of homogeneity in the physical and morphological properties, such as the particle size (diameter) or particle size range or distribution, of the intermediate products and/or the final product granules. Intermediate product granules are, for example the primary mix granules or the pre-mix granules.
Homogeneity has been suspected to be at least one of the critical factors assuring the quality and performance of the final product, and it is believed that product homogeneity (and inhomogeneity) relates to the mixing processes used. Thus, in the first stage of the known process, disparities may occur in the granule size and distribution (i.e. inhomogeneity may arise) because of the low binding properties or agglomeration properties between citric acid and magnesium oxide particles (caused by e.g the difference in densities of the two materials). Further, magnesium oxide is left on the mixer bowl, blades etc. (rather than being mixed with the citric acid). Thus, in the known process, extra magnesium oxide (“overage”) is included in the raw materials to compensate for losses during the blending process. The overage is typically over 10%. This leads to economic losses over longer periods and where larger quantities are produced. Additionally, longer processing times are entailed, and unhealthy amounts of dust may be produced during mixing.
In the premix stage, lack of homogeneity of the resulting granules may arise due to dissolution of some potassium bicarbonate in the granulation medium, water, and because of physical degradation (smashing) of the particles during mixing. This may have a detrimental effect on the final product. Further, long processing times, and multiple steps, are required to complete this stage of the process (which takes typically 15 to 24 hours).
Thus, there is a need for an improved manufacturing process.